Treatment Against Human Endogenous Retrovirus: A Possible Personalized Medicine Approach for Multiple Sclerosis
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Treatment Against Human Endogenous Retrovirus: A Possible Personalized Medicine Approach for Multiple Sclerosis Franc¸ois Curtin1,2 • Herve´ Perron1 • Raphael Faucard1 • Herve´ Porchet1,3 Alois B. Lang1
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Ó Springer International Publishing Switzerland 2015
Abstract Human endogenous retroviruses (HERV) represent about 8 % of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis–associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients. It possesses pro-inflammatory and myelinotoxic properties. The patterns of expression and pathogenic properties of MSRV-Env make it a relevant drug target for MS therapeutics—in particular for preventing neurodegeneration, a key component of progressive forms of MS. An immunoglobulin G4 monoclonal antibody (mAb), called GNbAC1, has been developed to neutralize this pathogenic target. After showing neutralizing effects in vitro and in mouse models of MS, GNbAC1 is now in phase II clinical development. MSRV-related biomarkers such as MSRV-Env and MSRV polymerase (MSRV-Pol) gene transcripts are overexpressed in the blood and cerebrospinal fluid of patients with MS. These biomarkers may have prognostic value for long-term MS evolution, and their transcription levels in blood decline during treatments with GNbAC1, which has also been reported in patients administered reference MS drugs such as natalizumab or interferon-b. GNbAC1 as a new MSRVEnv-antagonist mAb could be a specific and causal & Franc¸ois Curtin [email protected] 1
GeNeuro SA, 18 Chemin des Aulx, Plan-les-Ouates, 1228 Geneva, Switzerland
2
Division of Clinical Pharmacology and Toxicology Division, Geneva University Hospital, Geneva, Switzerland
3
Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
treatment for MS, with a particular application for progressive forms of the disease. For possible use in companion diagnostic tests, MSRV-associated biomarkers could open the door to a personalized therapeutic approach for MS.
Key Points GNbAC is an immunoglobulin G4 monoclonal antibody targeting a protein of endogenous retroviral origin. The target protein appears to play a critical role in the pathophysiology of multiple sclerosis. Biomarkers related to the target could play a role in companion diagnostic tests.
1 Introduction Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS), of unknown etiology. An autoimmune process underlies the pathophysiology of the disease; however; inflammation and neurodegeneration are closely associated during the disease: autoimmunity seems to predominate at the beginning of the disease evolution, while neurodegeneration prevails at the late stages and is associated with the progression of disability. The interrelations between both pathophysiological processes are complex and far from bein
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